Pharmaceutical compositions of paclitaxel, paclitaxel analogs or paclitaxel conjugates and related methods of preparation and use
Inventors
Demeule, Michel • Che, Christian • Regina, Anthony • Béliveau, Richard • GAGNON, Catherine • Castaigne, Jean-Paul • Gabathuler, Reinhard
Assignees
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Publication Number
US-8710013-B2
Publication Date
2014-04-29
Expiration Date
Abstract
Pharmaceutical compositions useful for hydrophobic agents paclitaxel, paclitaxel analogs and conjugates thereof (e g ANG1005) which do not contain Cremophor™ The compositions further comprise an optional tonicity agent, a buffering agent a bulking agent and a solubilizing agent which is not Cremophor™ Methods of preparing said compositions and of said compositions in the treatment of cancer are also included.
Core Innovation
The invention relates to CREMOPHOR-free pharmaceutical compositions that include paclitaxel or a paclitaxel analog as part of a conjugate comprising a polypeptide and the therapeutic agent conjugated to the polypeptide. The polypeptide comprises an amino acid sequence having at least 70% identity to AngioPep-1, AngioPep-2, or AngioPep-7. The composition is formulated with a tonicity agent, a buffering agent maintaining a pH of 4.5-6, a bulking agent, and a solubilizing agent that is not ethoxylated castor oil, and it contains 0.2 to 10% DMSO.
The pharmaceutical compositions further include DMSO together with a non-ethoxylated castor oil solubilizing agent. In particular embodiments, the solubilizing agent includes 12-hydroxystearic acid-polyethylene glycol copolymer. Representative formulations include ANG1005 with defined percentage ranges by non-water weight, including embodiments with ANG1005, buffer, bulking agent, 12-hydroxystearic acid-polyethylene glycol copolymer, and DMSO.
Formulation work is described for making a lyophilized product while controlling DMSO-related properties and preserving the solubilizing agent system. The description includes acidified DMSO prior to dissolving and lyophilization constraints to prevent cake collapse and achieve high purity. Stability and post-reconstitution results are reported for lyophilized product, including purity, assay, appearance, cloudiness, related substances, sterility, pH, water content, and DMSO content.
Claims Coverage
The provided material includes three independent composition claims. Across these independent claims, the main inventive features concern a CREMOPHOR-free formulation strategy for ANG1005 and paclitaxel/paclitaxel analog conjugates with defined component roles and specified DMSO levels, together with defined percentage ranges for specific excipient systems.
AngioPep polypeptide-conjugated paclitaxel or paclitaxel analog formulation
A composition comprising a conjugate comprising a polypeptide having at least 70% identity to AngioPep-1, AngioPep-2, or AngioPep-7, and a therapeutic agent selected from paclitaxel and a paclitaxel analog, wherein the therapeutic agent is conjugated to a polypeptide; a tonicity agent; a buffering agent that maintains a pH of 4.5-6; a bulking agent; and a solubilizing agent that is not ethoxylated castor oil, with 0.2 to 10% DMSO.
ANG1005 excipient composition with non-ethoxylated castor oil solubilizer and DMSO
A composition comprising ANG1005 0.1-5% by non-water weight, tonicity agent 1-15%, buffering agent 1-10%, bulking agent 0-15%, 12-hydroxystearic acid-polyethylene glycol copolymer 40-75%, and DMSO 0.2-10%.
ANG1005 excipient composition with defined buffer, bulking agent, and low DMSO
A composition comprising ANG1005 1.8-4.0% by non-water weight, buffer 0.1-6%, bulking agent 0.2-10%, 12-hydroxystearic acid-polyethylene glycol copolymer 80-95%, and DMSO 0.2-1%.
Across the independent claims, the inventive subject matter is a defined excipient system for ANG1005 and paclitaxel-conjugate formulations that uses a non-ethoxylated-castor-oil solubilizing agent and includes tonicity, a buffering agent maintaining pH 4.5-6, a bulking agent, and DMSO in specified ranges.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Cancer treatment.
Parenteral and non-parenteral administration routes.
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